BACKGROUND: Despite the proven effectiveness of many medications for chronic diseases, many patients do not refill their prescriptions in the required timeframe. OBJECTIVE: Compare the effectiveness of 3 pharmacist strategies to decrease time to refill of prescriptions for common chronic diseases. RESEARCH DESIGN/SUBJECTS: A randomized, controlled clinical trial with patients as the unit of randomization. Nine pharmacies within a medium-sized grocery store chain in South Carolina were included, representing urban, suburban, and rural areas and patients from a variety of socioeconomic backgrounds. Patients (n = 3048) overdue for refills for selected medications were randomized into 1 of 3 treatment arms: (1) pharmacist contact with the patient via telephone, (2) pharmacist contact with the patient's prescribing physician via facsimile, and (3) usual care. MEASURES: The primary outcome was the number of days from their recommended refill date until the patient filled a prescription for any medication relevant to his/her chronic disease. Prescription refill data were obtained routinely from the pharmacy district office's centralized database. Patient disposition codes were obtained by pharmacy employees. An intent-to-treat approach was used for all analyses. RESULTS: There were no significant differences by treatment arm in the study outcomes. CONCLUSIONS: Neither of the interventions is more effective than usual care at improving persistence of prescription refills for chronic diseases in overdue patients.